Abstract The objective of Project 5 is to define novel molecular mechanisms by which nuclear receptors modulate lipid and immune homeostasis. Given the central roles that metabolism and inflammation play in diseases such as atherosclerosis and diabetes, elucidating novel lipid and immune signaling pathways may uncover new opportunities for therapeutic intervention, and will advance our understanding of fundamental physiological and pathophysiological processes. Work from our group and others over the past 10 years has characterized the oxysterol-activated nuclear receptor LXR as a major regulator of cholesterol and fatty acid homeostasis that modulates the development of cardiovascular disease. However, the impact of LXRs on the major constituents of membranes phospholipids has not been rigorously investigated. During the current grant period, we identified a previously unrecognized biological function for LXRs. We found that LXRs dynamically remodel membrane phospholipids in response to metabolic signals through transcriptional induction of the gene encoding the enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3). Building on prior work in this PPG, we propose a series of molecular, cell biological and mouse studies to investigate new hypotheses regarding the roles of LXR and membrane phospholipid composition in the control of lipid metabolism and inflammation. Specific Aim 1 is to elucidate the role of Lpcat3-dependent phospholipid remodeling in lipid metabolism. We hypothesize that regulation of Lpcat3 activity and membrane phospholipid composition by LXRs in response to changing sterol levels is a key mechanism for the maintenance of cellular lipid homeostasis. Specific Aim 2 is to determine the role of the LXR-Lpcat3 pathway in inflammation and the endothelial cell response to oxidized phospholipids. We hypothesize that the ability of LXR signaling to remodel the cellular fatty acids and phospholipid pools impacts inflammatory signaling by multiple mechanisms. Specific Aim 3: To determine the role of the LXR-Lpcat3 pathway in atherosclerosis. We hypothesize regulation of lipid metabolism and inflammation by the LXR-Lpcat3 pathway impacts the development and/or progression of atherosclerosis. This application builds upon and extends the productive collaborations of our PPG in the current grant period. Dissecting the molecular pathways that control lipid metabolism and inflammatory responses is central to the overall theme of this PPG application and has important implications for cardiovascular disease.